The goal of this five-year training award is to become a patient-oriented researcher in neuroAIDS. Training and research will include: 1) characterizing HIV neurocognitive impairment (HNCI) using calibrated blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI); 2) assessing the impact of combination antiretroviral therapy (cART) on calibrated BOLD fMRI. This proposal will delineate associations between calibrated BOLD fMRI and surrogate cerebral spinal fluid (CSF) markers of inflammation and neuronal/glial injury. My goal is to create a non-invasive neuroimaging tool for early detection and treatment of HNCI. Training will include courses and mentoring in neurovirology, neuropsychology, and advanced fMRI methods. HNCI is characterized by impairments in episodic memory, executive dysfunction, and psychomotor slowing. Even mild HNCI interferes with activities of daily living and the ability to become fully integrated into society. The central nervous system (CNS) can serve as a protected reservoir with the blood-brain barrier (BBB) shielding HIV from immunologic and pharmacologic defenses. cART has decreased the incidence and severity of HNCI but not its prevalence. The degree of CNS penetration by cART may affect HIV reservoirs. A cross sectional project will study 20 HIV- controls and 60 HIV+ patients with a range of cognitive impairment from neurocognitively normal (NN) to mild neurocognitive disorder (MND) to HIV associated dementia (HAD). It will test whether calibrated BOLD fMRI measures of cerebral blood flow (CBF) and oxygen metabolism (CMRO2) are associated with cognitive deficits. Correlations will be performed between calibrated BOLD fMRI and CSF biomarkers of inflammation and neuronal/glial injury. The impact of cART on calibrated BOLD fMRI and CSF biomarkers will be assessed longitudinally in an additional 20 HNCI patients before and 16 weeks after starting individualized antiretroviral regimens with different degrees of CNS penetration. This study will answer the following questions: 1) Do CBF and CMRO2 responses to a standard neural activation task change with degree of HNCI? 2) Does calibrated BOLD fMRI change after initiation of cART? In particular, does better CNS penetrating cART produce greater improvements? 3) Are calibrated BOLD fMRI changes associated with pathogenic changes in CSF biomarkers of inflammation and neuronal/glial injury? At the conclusion of this five year research training the applicant will be prepared for a productive career as a R01 level patient oriented investigator in neuroAIDS.